AU684966B2 - Pharmaceutical preparation with a hydrophobic active substance and an effervescent system, and process for preparing said preparation - Google Patents

Abstract

PCT No. PCT/EP95/01904 Sec. 371 Date Dec. 17, 1996 Sec. 102(e) Date Dec. 17, 1996 PCT Filed May 19, 1995 PCT Pub. No. WO95/34284 PCT Pub. Date Dec. 21, 1995A pharmaceutical formulation includes a hydrophobic active substance, an effervescent system, and at least two surfactants. Each of the surfactants is selected from a different group selected from the following three groups: phospholipids, polysorbates, and esterified sugars. The formulations provide improved dispersion and bioavailability of hydrophobic active substances.

Description

O PI DATE 05/01/96 APPLN. ID 27497/95 AOJP DATE 15/02/96 PCT NUMBER PCT/EP95/01904 I AU9527497 (51) Internationale Patentklasslflkatlon 6 (11) Internationale Verilffentlhungsnummer: WVO 95/34284 A61K 900 Al (43) Internationales Ver~iffentlichungsdatumn: 21, December 199$ (21.12.95) (21) Internationales Akctenzeichen: PCTIEP95101904 (81) nestlmmungsstaaten.- AM, AT, AU, BB, BO, BR, BY, CA, CH. CN, CZ, DE, DK, EE, ES, Fl, GB, GE, HU, IS, JP, (22) lntcrnationales Anmeldedatuin: 19. Mal 1995 (19.05.95) KB, KG, KP, KR, KZ, LK, LR, LT. LU, LV, MD, MG, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, ITr, UA, UG, US, UZ, VN, curopisches Prloritiitsdaten: Patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IB, IT, LU, 1890/94.0 15. Juni 1994 (15.06.94) CH MC, NL, PT, SE), QAPI Patent (BE, BJ, C, CO, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), ARIPO Patent (KB, MW, SD, SZ, UG).

(71)(72) Anmelder und Erfinder: GERGELY, Gerhard [ATIAI; Gartengasse 8, A. 1053 Wien (AT).

Veritfentliehit (72) Erllnder; mid Mit internationalen: Recherchenberichu'.

Erllnder/Anmelder (nur ir US): GERGELY, Irmgard Vor Ablauf derfar Anderungen der Ansprilche zigelasscnen (AT/ATI; Gartengasse 8, A-1053 Wien GERGELY, Frist. Verdffenlichung ivird wiederholl falls Anderungen Thomas [AT/AT]; Gartengasse 8, A-1053 Wien eintreffen.

(74) Anwalt: PATENTBODRO DR. BOCHEL; Letzanaweg 25, FL- 9495 Triesen (LI).

(54) Title: PHARMACEUTICAL PREPARATION WIT H A HYDROPHOBIC ACTIVE SUBSTANCE AND AN EFFERVESCENT SYSTEM, AND PROCESS FOR PREPARING SAID PREPARATION (54) Bezeichnung: PHARMAZEUTISCHE ZUBEREITUNG MIT EINEM NYDROPHOBEN WIRKSTOFF UND BINEM BRAUSESYS- TEM, SOWIE VERFAHREN ZUR HERSTELLUNG DER ZUBEREITUNG (57) Abstract The invention concerns pharmaceutical effervescent tablets with at least one hydrophobic active substance, such as for example loratadine or cisapride, and a surfactant, These effervescent tablets advantageously contain at least two different surfactants or emnulsifiers, in particular from the group comprising sugar esters, polysorbates and phospholipids, At least one of the emulsifiers can be present in the mixture in the form of granules separately from the effervescent system and/or active substance granules, Preferably, the active substance is also precipitated in the form of separate active substance granules -for example by means of a binder, such as for example polyvinylpyrrolidone on the surface of a suspended substance or anti-adhesive substance, such as for example Aerosile or Avicel@. The active substance can, moreover, contain at least one of the effervescent components and/or a filler which Preferably comprises at least one of the following compounds: higher alcohols, e~g. mannitol, sorbitol or lactose; hydrocolloids, such as maltodextrin or dextrin; and starch.

(57) Zusamnienfassung Pharmazeutische Brausetabletten mit wenigstens einemn hydrophoben Wlrkstoff, wie z.B. Loratadin oder Cisaprid, und einem Tensid enthalten zweckrnlissig wenigstens zwei verschiedene Tenside bzw. Emulgatoren, insbesondere aus der Gruppe der Zuckerester, der Polysorbate und der Phospholipide. Wenigstens einer der Emulgatoren kann getrennt yam Brausesystem undloder Wirkstoffgranulat in cinemn eigenen Granulat In der Misehung vorliegen. Auch der Wirkstoff ist vorzugsweise in einem eigenen Wirkstoffgranulat -etwa mit Hilfe cines Bindemittels, wie z.B. Polyvinylpyrrolidon auf der Oberfiulche eines Schwebstoffes bzw. Antiklebstoffes, wie z.B, Aerosil® oder AvicelO, niedergeschlagen und kann ausserdemn wenigstens cine der Brausekomponenten und/oder einen Falhistoff enthalten, der vorzugsweise wenigstens eine der folgcnden Verbindungen umfasst: hi~here Alkohole, zB. Mannit, Sorbit oder L.actose;' Hydrokolloide, wie Maltodextrin oder Dextrine; Stllrke.

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Pharmaceutical formulation containing a hydrophobic active substance and an effervescent system, and process for the preparation of the formulation The invention relates to a pharmaceutical formulation according to the precharacterizing clause of Claim 1. In the case of the pharmaceutical formulation containing an effervescent system, hydrophobic active substances give rise to considerable difficulties, which are even greater in the case of loratadin: apart from the formation of active substance rings on the glass, the dissolution of an effervescent tablet is also substantially slowed down. A particular composition of the effervescent system, as may be useful, for example, for acid-, alkali- and/or metalsensitive active substances, is of no further assistance here.

For example, loratadin is virtually completely water-insoluble (2.5 mg/litre) and has a very strongly hydrophobic character. It is thus extremely poorly wettable and therefore difficult to suspend. Its fine particles furthermore have the tendency to form a film on the water surface, to creep up the glass wall to a pronounced extent and to adhere relatively strongly there; the coarser particles sink to the bottom; in addition, dissolution of a conventional, loratadinc-,taining effervescent tablet gives rise to foam formation, resulting in dissolution behaviour which is unsuitable with regard to marketing. Moreover, up to of the active substance are lost as a result of adhesion to the glass.

A further problem is the small dose of 10 mg of active substance per tablet, which, in an effervescent tablet, must achieve the content uniformity required in uf~ A 0 ^f< -e<TO accordance with the pharmaceutical guidelines. This requirement, too, cannot be met by mixing the active substance with an effervescent base. It is also desirable to have a small effervescent tablet of about 1 to 1.5 g, which makes the problem more difficult to solve.

In order to improve the poor suspension properties of loratadin, attempts have already been made, according to EP Al 241 469, to treat the active substance with wetting agents, such as docusate sodium or sodium laurylsulphate, with or without a binder. It was found that the use of these wetting agents did not achieve the aim, either by direct application of the surfactant to the active substance or to a mixture of the active substance with a filler, such as mannitol or sorbitol, or by addition of the surfactant to the effervescent base. On dissolution of the effervescent tablet, the active substance treated in this manner and present therein exhibited excessively strong foam formation, which could not be substantially reduced even by adding an antifoam, and another disadvantage observed was that the active substance is not suspended but collects in the foam on the water surface.

It is the object of the invention to provide a pharmaceutical formulation for hydrophobic active substances, in particular for loratadin, which takes into account the physical behaviour of such active substances. However, there must be no other undesirable side effects, such as, for example, foam formation. Furthermore, even small amounts of active substance must be capable of being distributed as uniformly as possible in an effervescent tablet, and the weight of the effervescent tablet should be capable of being kept as low as possible.

0 4' LU y <4' I I -Ed These objects are achieved and problems solved for the first time surprisingly by the measures described in the characterizing clause of Claim 1; particular embodiments and further developments of the inventive concept are described in the characterizing clauses of the dependent Claims. The invention is first illustrated in more detail using loratadin as an example. For the purposes of the invention, "surfactant" is to be understood as meaning the wetting agents which are in particular (not but exclusively) ionic, are conventionally used in pharmacy and reduce the surface tension, as docusate sodium, sodium laurylsulphate, etc. It is particularly expedient if, in addition to such a "surfactant", the formulation according to the invention contains at least one "emulsifier" or, instead of this, two "emulsifiers".

"Emulsifiers" are to be understood as meaning the wetting agents serving in pharmacy as conventional excipients for achieving water-in-oil or oil-in-water emulsions, in particular sugar surfactants, phospholipids and polysorbates.

According to the invention, methods are alsoproposed for suppressing the foam formation, suspending the active substance during dissolution of the effervescent tablet and preventing it from adhering to the glass. This is achieved by the measure of the preparation of suitable granules of active substance, which preferably contain one emulsifier or two different emulsifiers in combination and are added to the effervescent base.

However, the measure of loading a suspended substance with an insoluble active substance still has a slight disadvantage, namely that the particles will become too heavy and show a tendency to sink to the bottom on dissolution of the tablet. Furthermore, the required uniform distribution of the active substance in the effervescent tablet cannot be achieved owing to the frequently low dose of these substances, However, this problem, too, could be solved by anchoring the active substance to an additional filler which is not too freely soluble. As a result of this "dilution", it is possible to achieve uniform distribution in the tablet and also decisively to improve the suspension behaviour, since the active substance is anchored both to the suspended substance and to the filler. The granules of active substance thus contain a neutral substance as vehicle or filler and a suspended substance, such as Aerosil(R) (a highly dispersed, "pyrogenic" silicic acid) and a binder, by means of which the active substance is bound to the vehicle or filler.

In order therefore to be able to incorporate hydrophobic active substances into an effervescent tablet without having to accept their negative behaviour on subsequent dissolution, it is particularly expedient to prepare special phases, for example to introduce an active substance-specific, special combination of suspending agents or surface-active substances into the effervescent tablet and preferably additionally to prepare an active substance phase. However, experience has shown that the preparation of an active substance phase alone is not sufficient to suppress the unattractive properties of the active substances on dissolution of the effervescent tablet.

There are two possibilities for the preparation of the granules of active substance: either the active substance is dissolved and is applied to a suspended substance or S 2o antiadhesive as a vehicle which is suspended on dissolution of the effervescent tablet in water, such as, for example, Aerosil (a highly dispersed, "pyrogenic" silicic acid) or Avicel(R) (microcrystalline cellulose); or the vehicle is mixed *o [Ni"\ibaa00933:VR with the active substance and the active substance is the superficially dissolved, preferably by means of a binder-containing solvent, so that it can attach itself to the vehicle. If the vehicle/filler is also at least superficially dissolved by the solvent, it may be possible to dispense with the binder. Thus, an active substance phase in which the active substance is either superficially dissolved or dissolved, preferably together with a binder, in particular polyvinylpyrrolidone, is prepared. The active substance is coprecipitated with the binder on the surface of the suspended substance or antiadhesive and is thus kept very substantially in suspension on dissolution of the effervescent tablet. As already mentioned, however, the active substance is preferably "bound" to the mixture of a suspended substance with a filler, such as mannitol, lactose, maltodextrin or sucrose, as a vehicle.

The vehicle may consist either of lactose plus Aerosil(R) (a highly dispersed, "pyrogenic" silicic acid) and sodium bicarbonate, for example in a loratadin phase, or may consist of Aerosil(R) (a highly dispersed, "pyrogenic" silicic acid) alone, as, for example, in the case of cisapride. However, in order optimally to suspend this phase in the effervescent solution and to compensate the above-mentioned negative properties, it is necessary to use at least two surface-active substances in the total formulation, for example in the case of cisapride: docusate sodium and Metarin(R) P (a pulverulent phosphoaminolipid low in foreign fats); in the case of loratadin: Epikuron(R) (also a 20 lecithin) and a DK-Ester(R) (a sugar fatty acid ester), all of which have dispersant properties.

Emulsifiers from the group consisting of the sugar esters DK-Ester(R)) and polysorbates Tween(R)) on the one hand and from the group consisting e *f- [N:\libaa]00933:JVR Ir 6 of the phospholipids lecithins, phosphatidylcholine, Metarin(R), Epikuron

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phosphatidylethanolamine, phosphatidylinositol, etc.) on the other hand can either be incorporated in the granules of active substance or applied, separately from these, directly to the effervescent granules or to a neutral substance and then added to the granules of active substance and effervescent granules. However, it has been found that, as a result of granulation with the binder, the action of the emulsifier in the granules of active substance is not quite so good as when it is added directly in solid form to the final mixture.

Particularly for the liquid or pasty phospholipids, emulsifier granules are preferably prepared separately from the effervescent base and from the granules of active substance, suitable vehicles for the emulsifier being virtually all fillers suitable for an effervescent tablet, such as higher alcohols, e.g.

mannitol, sorbitol or lactose, or hydrocolloids, such as maltodextrin or dextrins, or starch. The amount to which the emulsifier is applied is not critical; however, it should on the one hand be sufficient for the required incorporation in an effervescent tablet; on the other hand, the granules should be such that they are not too greasy. Both require at least a ratio of 1 part of emulsifier to 10 parts of vehicle.

In the case of the emulsifier phase, the emulsifier, for example the phosphatidylcholine, is applied to a filler by means of a solvent or as an aqueous suspension, in order to achieve as far as possible a ubiquitous distribution within the tablet.

As a result of the above-mentioned combination, according to the invention, of two surfactants or

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-ai emulsifiers, on the one hand from the group consisting of the phospholipids and on the other hand from the group consisting of the sugar esters (in particular of edible fatty acids), the creeping of the active substance up the glass wall is reduced from originally at least 10% to not more than Among the sugar esters, there are those which are more hydrophilic and those which are more lipophilic. It is interesting that, in the case of loratadin, DK-EsterR) F 50, which in principle is a lipophilic sugar ester, gives better results than the hydrophilic sugar esters, e.g. DK- Ester(R F 140. This may be due to the fact that the foaming power of this DK-Ester(R) is the lowest.

Example 1: parts by weight of loratadin are mixed with 150 parts by weight of mannitol and 2.5 parts by weight of Aerosil(R) and heated to 55 0 C while mixing. 5 parts by weight of polyvinylpyrrolidone and 0.5 part by weight of a polysorbate emulsifier TweenR) are dissolved in 30 parts by weight of ethanol and applied to the mixture while stirring. Mixing is carried out for 5 minutes for uniform wetting; the granules are then dried by means of low pressure at a temperature of 50 0 C. The resulting granules of active substance are sieved to 0.2 mm and mixed with 1000 parts by weight of an effervescent base to which 2.4 parts by weight of DK-Ester(R) and flavours and sweeteners have been added.

The granules are compressed into 1.3 g tablets.

Example 2: 200 parts by weight of pulverulent lactose are heated to 55 0 C. 10 parts by weight of loratadin are dissolved in 45 parts by weight of ethanol, followed by 10 parts by weight of polyvinylpyrrolidone and parts by weight of Aerosil(R This solution is .applied to the lactose while stirring, after which

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mixing is carried out for 10 minutes for uniform distribution. The mixture is then dried by means of reduced pressure at 50 0 C and sieved to 0.1 mm. The granules of active substance are added to 650 parts by weight of an effervescent base, to which 0.2 part by weight of phosphatidylcholine has been applied.

Furthermore, 2 parts by weight of sugar ester and 200 parts by weight of a filler, as well as flavours and sweeteners, are added to the mixture, and the resulting mixture is finally compressed into tablets.

In a modification of this method, the phosphatidylcholine Epikuron(R)) is applied together with the binder and the active substance to the vehicle. However, the suspension effect is then no longer quite as good.

Even better dissolution behaviour of the active substance phase in the effervescent tablet can be achieved if small amounts of sodium bicarbonate are introduced into the granules, with the result that, since the sodium bicarbonate reacts with the acidic effervescent solution on dissolution of the tablet, coarser particles disintegrate and bring the active substance into suspension.

Example 3: parts by weight of loratadin are dissolved in 25 parts by weight of ethanol; 10 parts by weight of polyvinylpyrrolidone are then dissolved and 5 parts by weight of Aerosil(R) and 0.8 part by weight of sodium bicarbonate are introduced into the solution, which is heated to 60C. This solution is applied to 100 parts by weight of lactose while stirring, and is mixed for minutes for uniform distribution; the mixture is then dried and is sieved to 0.2 mm. These granules of ~active substance are mixed with 850 parts by weight of u-I

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-s effervescent base and with a mixture of 50 parts by weight of mannitol and 2 parts by weight of a sugar ester of edible fatty acids and with fillers, sweeteners and flavours and 50 parts by weight of an emulsifier phase (consisting of 49.8 parts by weight of mannitol and 0.2 part by weight of phospholipids) and the mixture is compressed into tablets.

Example 4: 5 parts by weight of AerosilR), 10 parts by weight of loratadin and 100 parts by weight of lactose are heated to 50 0 C while mixing. A solution consisting of 10 parts by weight of polyvinylpyrrolidone and 37 parts by weight of ethanol, in which 0.8 part by weight of sodium bicarbonate is suspended, is then applied to the mixture in 3 steps, while stirring. In the Ist step, 55 to 60% of the solution are applied while stirring and distributed for minutes, after which the solvent is partly removed by drying by means of low pressure at 100 mbar. The 2nd part of the solution, about 42%, is then applied while stirring, and mixing is carried out for 2 minutes for uniform distribution, after which the solvent is again partly removed by means of low pressure at 100 mbar.

The remaining part of the solution is then applied while stirring, and final drying is carried out by means of low pressure.

The resulting granules of active substance, together with 50 parts by weight of emulsifier granules (consisting of 49.8 parts of mannitol and 0.2 part by weight of lecithin) and 850 parts by weight of effervescent base, sweetener and flavour and 100 parts by weight of sorbitol and a mixture of 2.4 parts by weight of sugar ester of an edible fatty acid with parts by weight of mannitol, are compressed into 1 .25 g effervescent tablets.

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Example With the same composition as Example 4, for example, it is also possible to introduce a portion of Aerosil(R) into the solution and to add a portion of polyvinylpyrrolidone in dry form to the mixture of Aerosil(R) and lactose. This mixture is then further treated as in Example 4.

Example 6: Preparation of the emulsifier granules: parts by weight of mannitol are heated to 0 C while stirring. A solution of 0.2 part by weight of Epikuron() in 12 parts by weight of ethanol is prepared and is applied to the mannitol while stirring.

Drying is then carried out by means of low pressure at a product temperature of 50 0 C, and the granules are sieved to 0.3 mm.

Example 7: Preparation of the cisapride phase: parts by weight of cisapride are premixed with 10 parts by weight of Aerosil(R), heated to and moistened with an ethanol/acetone solution (2:18) which contains 1 part by weight of propylene glycol, 1 part by weight of docusate sodium and 2 parts by weight of polyvinylpyrrolidone. The solution is distributed for 5 minutes while stirring; drying is then carried out by means of low pressure while stirring. The granules of active substance are sieved to a particle size of 0.1 mm.

Preparation of the effervescent granules: 790 parts by weight of citric acid, 16 parts by weight of malic acid and 9.5 parts by weight of saccharin sodium are heated to 60 0 C while mixing.

4.6 parts by weight of a solution consisting of 4 I i II part by weight of sodium citrate, 0.7 part by weight of citric acid, 2.5 parts by weight of water and 0.9 part by weight of sorbitol are then applied and are distributed for 3 minutes while mixing. 274 parts by weight of sodium bicarbonate and 2 parts by weight of aspartame are then added and are allowed to react briefly. Thereafter, 62 parts by weight of sodium carbonate are admixed and the product is dried by means of low pressure while stirring slowly. The product is sieved to a particle size of 1.6 mm.

Preparation of the end mixture: 2 parts by weight of Metarin P mixed with 100 parts by weight of lactose and 50 parts by weight of maltodextrin, 150 parts by weight of mannitol and parts by weight of lemon flavour are mixed with the active substance phase and with the effervescent granules with the addition of an antifoam (0.1 part by weight of polysiloxane applied to 50 parts by weight of mannitol), and the mixture is then compressed into tablets.

Example 8: Preparation of the cisapride phase: 270 parts by weight of mannitol and 5 parts by weight of Aerosil() and 10 parts by weight of sodium bicarbonate are mixed while stirring and are heated to 0 C. 2 parts by weight of polyvinylpyrrolidone, 0.8 part by weight of docusate sodium, 1 part by weight of propylene glycol and 10 parts by weight of cisapride are then dissolved in 2 parts by weight of ethanol and parts by weight of 2-butanone; this solution is applied in 2 parts to the vehicle, after which intermediate drying is carried out at 100 mbar and the granules are then finally dried and are sieved to a particle size of 0.2 mm.

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Preparation of the effervescent granules: The effervescent granules are prepared as described under Example 7.

Preparation of the emulsifier granules: parts by weight of mannitol are heated to 0 C; 0.4 part by weight of Metarin F is then dissolved in 2 parts by weight of ethanol and the solution is applied to the mannitol while stirring. The solvent is then removed by drying by means of low pressure, and the emulsifier granules thus prepared are sieved to 0.3 mm.

Preparation of the end mixture: The three phases are mixed with the addition of an antifoam (0.1 part by weight of polysiloxane applied to 50 parts by weight of mannitol), 50 parts by weight of maltodextrin and 40 parts by weight of orange flavour and then compressed into 1.6 g tablets.

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Claims (21)

1. Pharmaceutical formulation, containiz hydrophobic active substance, an effervescent system and at least two substances selected from the group consisting of surfactants and emulsifiers, characterised in that: a. one of the at least two substances is at least one emulsifier selected from the group consisting of phospholipids, polysorbates and esterified sugars, and b. the other of the at least two substances is either an emulsifier different from the emulsifier referred to in a) above and is selected from the group consisting of phospholipids, polysorbates and esterified sugars, or is an ionic surfactant.

2. Formulation according to claim 1, characterised in that it contains loratadin or cisapride as the active substance,

3. Formulation according to claim 1 or claim 2, characterised in that one of the at least two substances is at least one surfactant, being docusate sodium or sodium laurylsulfate, or at least one emulsifier from the group consisting of phospholipids, polysorbates and esterified sugars.

4. Formulation according to any one of claims 1 to 3, characterised in that at least one of the emulsifiers is present in the formulation as separate granules separated from the effervescent system and/or granules of active substance. Formulation according to any one of the preceding claims, characterised in that the active substance, in separate granules of active substance, is deposited on the surface of a suspended substance or antiadhesive.

6. Formulation according to claim 5, characterised in that the suspended substance or antiadhesive is Aerosil or Avicel.

7. Formulation according to claim 5 or claim 6, characterised in that the active 25 substance, in separate granules of active substance is deposited on the surface of a suspended substance or antiadhesive with the aid of a binder.

8. Formulation according to claim 7, characterised in that the binder is polyvinylpyrrolidone.

9. Formulation according to any one of claims 5 to 8, characterised in that the 30 granules of active substance additionally contain at least one of the effervescent components and/or a filler. Formulation according to claim 9, characterised in that the filler comprises at Sleast one of the following compounds: an alditol, a hydrocolloid or starch.

11. Formulation according to claim 10, characterised in that the alditol is mannitol, sorbitol or lactose.

12. Formulation according to claim 10, characterised in that the hydrocolloid is maltodextrin or dextrin. tN:\libaa]00933JVR 14

13. Formulation according to any one of the preceding claims, characterised in that at least one emulsifier is applied to the components of the effervescent system or to granules containing an effervescent component and/or to the granules of active substance.

14. Pharmaceutical formulation, containing a hydrophobic active substance, an effervescent system and at least two surfactants or emulsifiers, substantially as hereinbefore described with reference to any one of the examples. Process for the preparation of granules of active substance for a formulation according to any one of claims 4 to 13, characterised in that a solution lo which contains the active substance and preferably at least one binder and/or at least one emulsifier is applied to the particles of suspended substance and/or filler particles, uniformly distributed and heated, after which the solvent is removed by drying, preferably at low pressure, and the resulting granules are sieved to the desired particle size.

16. Process according to claim 15, characterised in that the solution contains at least one binder and/or at least one emulsifier.

17. Process according to claim 15 or claim 16, characterised in that the solvent is removed by drying at low pressure.

18. Process for the preparation of granules of active substance for a o: 20 formulation according to any one of claims 4 to 13, characterised in that the active substance mixed with the suspended substance and/or filler is wet with a solution and is uniformly distributed over the particles, which solution contains at least one Sbinder and/or at least one emulsifier, after which granulation is carried out while stirring, drying is carried out, and sieving is carried out to the desired particle size. S 25 19. Process according to claim 18, characterised in that the drying is carried So out at low pressure.

20. Process for the preparation of emulsifier granules for a formulation according to any one of claims 4 to 13, characterised in that a solution which oO*o contains at least one emulsifier and optionally at least,,ne binder is applied to the 30 filler, after which granulation is carried out while stirring, dry,,Ig is carried out, and sieving is carried out to the desired particle size.

21. Process according to claim 20, characterised in that the drying is carried out at low pressure.

22. Process according to any one of claims 15 to 21, characterised in that the filler comprises at least one of the following compounds: a higher alcohol, a hydrocolloid or starch. 8N L( N:libu\07869

23. Process according to claim 22, characterised in that the higher alcohol is mannitol, sorbitol or lactose

24. Process according to claim 22, characterised in that the hydrocolloid is maltodextrin or dextrin. Dated 14 January, 1997 GERHARD GERGELY Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON o N:ibiAO7S6O INTEUNATIONAL SEARCII 1IORT Wen ApplitetionNo PCT/EP 95/01904 rrr~ A. CLASSIFICATION OF SUBJECT MATTER IPC 6 A61K9/00 Accordin to Intemalton, l Patent Classificaion (IPC) or to both national clanafictinn and IPC. Acodngt neraim1 aetClsiiato IP rt bt aonlcasiiain n P B. FIELDS SEARCHED Minimum documentaton searched (classificauon system followed by classification symbols) IPC 6 A61K Docunentation searched other than minimum documentation to the extent that such documents arc included in the fields searched Electronic data base consulted durng the internatonal search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A EP,A,O 228 164 (THE BOOTS COMPANY PLC) 8 1-10 July 1987 see claims 1-10 see page 2, line 10 line see page 2, line 29 line 51 see page 3, line 5 line 9 see page 3, line 18 line 22 see page 3, line 32 line 47 A WO,A,94 10994 (THE BOOTS COMPANY PLC) 26 1-10 May 1994 see page 8, line 25 page 9, line 12 see page 10, line 3 page 11, line 2 S Further documents are listed in the continuation of box C, y Patent family members are listed in annex. *Special categories of cited documents: "T later document published after the international filing date or priority date and not in onflict with the aplication but document defining the general state of the art which is not cited to understand the principlc or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the intemational search report 3 October 1995 13- 1 0-9 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31-70) 340-2040, TX. 31 651 po n, Ventura Amat, A Faix 3170) 340-3016 e Form PCT/ISA/210 (tecena tihMt) (July 1992) INTERNATIONAL SE~ARCHI Informnation On patent family mctnbcrs RE OR0!1 Inen Application No PCT/EP 95/01904 Patent document I Publicaion Patent family I Pubic~ation cie nsarch report d ate -Tmember(s) date EP-A-0228164 08-07-87 AU-B- AU-B- CA-A- DE-A- IE-B- JP-C JP-B- JP-A- KR-B- US-A- 594265 6509186 1275933 3683270 59135 1726293 4015204 62135418 9402659 4806358 01-03-90 21-05-87 06-11-90 13-02-92 12-01-94 19-01-93 17-03-92 18-06-87

28-03-94 21-02-89 WO-A-94 10994 26-05-94 AU-B- 5466094 08-06-94 Forin PCTIISA/2l 0 (patent family annex) (Juy 1992) IWrIRN AIIONALER 11tCHERCUiENIMU~CI-17 Inten %ale$ Akteazeidelin IPCT/EP 95/01904 A. KIASSIFIZIIERUNG DES ANM12LDUNGSGEGENSTANDES IPK 6 A61K9/OO Nach der Internatianalen I'atntiasttllkation (IPK) odcr nach der nationalen Klamfilkation tend der IPK B3. RECH-ERCHIERT3 GEDIETI3 Recherchierter MindestprUstaff (Klassifikatiormystemn und Kiassilikatianssymbole) IPK 6 A61K Recherchierte aber nscht zumn Mindestprilfstoff gehdrcnde Verdffentiichungen, sowelt diese unter die recherehscrten Gebicte fallen W~hrend der intemateanalen Recherche konsultierte elektronischc Datenbank (Name der Datenbank und evti. verwendete Suchbcgeiffe) C. ALS WESENTLICH ANGESEHENE UNTERLAGEN Kategone* Berzeichnung dcr Verdlfentltchung, saweit erforderlich unter Angabe der in Betracht konrnenden Teile Mier. Ansprch Nr. A EP,A,O 228 164 (THE BOOTS COMPANY PLC) 8. 1-10 Juli 1987 siehe AnsprUche 1-10 siehe Seite 2, Zeile 10 Zeile siehe Seite 2, Zeile 29 Zeile 51 siehe Seite 3, Zeile 5 Zeile 9 siehe Seite 3, Zeile 18 Zeile 22 siehe Seite 3, Zeile 32 Zeile 47 A WO,A,94 10994 (THE BOOTS COMPANY PLC) 26. 1-10 Mai 1994 siehe Seite 8, Zeile 25 Seite 9, Zeile 12 siehe Seite 10, Zeile 3 Seite 11, Zeile 2 FlWeitere Verdffentiichungen sind der Fosisetzung von Feld C zu 171 Siehe Anhang Patentfanilie entnehmen J Beandre Ksegnen on ngeebe'en er~fndihungn T Sptere Verdffentlichung, die nach demn internationalen Anmeidedlatum Vcr6lfentiichung, die den aligerneinen Stand der Tchnik dlefinier, r dem PriontitsdatUmn verdlfeutilcht worden ist tend mit der aber rult als besonelers bedcutsam anusehen ist Anmeldung nicht kollidiert, sondemn nur zumVeretindnis des der ffiteres Dokument, das jedoch eret am oder nach dem internatonalcrn Erlidung zgxudelgdn Prnleodrdrterzgedeigne Antmeldedlatum verolfcntlicht warden ist W Ver6ffentlichung von besondertr Bedeutung; dic beanspruchte Erfinduni LVcrl~ffentlichung die geege it, inen Priorititsanspnseh zweifelhaft er- kann allein auf~ed dieter Ver~ffntiichung nicht als neu oder auf scheenen zu Ias'.n, oder du C i das Verd flentlichungsdaturncuter cifinderiseher W1tegkeet benshiend betraehtet werden anderen um Recherchenbericht genannten Ver6ffentlichung belegt werden Ver~fentlichung von besonderer Bedeutuig; die beanspnechte Erlindung soil oder die aus elnemn anderen besanderen Gnsnd angegeben ist (wie kann micht ais auf erfinderiecher Tigkeit beruhend betrachtet augerir) werden, wean die Verdfftntlichun& mit einer oder meltreren anderen Ver~fentlichung, die sich aeut eine mfendliche Oftenbarung, Vereintlichungen dietr Kategone in Vcrbindung gebracht wirt tend eine Benutzung, esne Aussteliunig ader andere Malinsimen bezieht diese Verbindung Mr elnen Fachmn nalicliegen ist Verblfentlichung, die var dem nematianalen, Anmeidediatumn, aber nach W~Vr~ffentlichung, die Mitglied dereelben Patentfarnile it demn beanspnichten Priontitsdatum veroffentlicht warden st Datum des Abschiusses der nternationalen Rechserche Absendedatumn des intemnationalen Recherchenbenichts 3. Oktober 1995U %9 Name send Postanscheift der Interniateanale Recherchenbehbrde Bevallindchugter iBediensteter Euraplisches Patentamt, P.B. 58 8S Patentlaan 2 NL 2280 HV Rijswijk Tel. (+i31-70) 34D-2040, Tx. 31651epo n,Vetr Am t A Faxe 31.70) 340-3016Vetr m ,A Porenblatt PCTIISA/210 (Blatt 2) (JUll 1992) INTiR NATriONALER RECJIERCIIENORICI T Angaben zu Verdffntlichungen, die zur NOWbc I'4tci'UAmilie Schoren lntcn Wesc Aktocnzclhto POT/EP 95/01904 I Im Recherchenbericht Datum der IMitglicd(er) der Datum der angefuhrtes Patentdokument Verdifentlich ung JPatentfamllc Vcrbfifentichung EP-A-0228164 08-07-87 AU-B- 594265 01-03-90 AU-B- 6509186 21-05-87 CA-A- 1275933 06-11-90 DE-A- 3683270 13-02-92 IE-B- 59135 12-01-94 JP-C- 1726293 19-01-93 JP-B- 4015204 17-03-92 JP-A- 62135418 18-06-87 KR-B- 9402659 28-03-94 US-A- 4806358 21-02-89 WO-A-9410994 26-05-94 AU-B- 5466094 08-06-94 Formblatt PCTIISA/21D (Anhang Patentfinmilie)(Juli 1992)